Date of Completion

8-11-2017

Embargo Period

8-11-2017

Advisors

Jose Manautou, Brian Aneskievich, Yvonne Will

Field of Study

Pharmaceutical Science

Degree

Master of Science

Open Access

Open Access

Abstract

The peroxisome-proliferator activated receptors (Ppars) are a family of ligand-dependent nuclear receptors, which promote transcriptional activation of target genes. Pparα regulates genes involved in hepatic fatty acid transport, uptake and metabolism. Several of these target genes are upregulated by hypolipidemic fibrate-type drugs. Clofibrate (CFB) is a prototype for this class, and a well-known Pparα activator. CFB treatment also prevents liver injury by acetaminophen (APAP) in a Pparα-dependent manner. Similarly, nuclear factor erythroid 2-related factor 2 (Nrf2) is an important genetic determinant of susceptibility to APAP hepatotoxicity. The purpose of this study was to analyze the potential interaction between Pparα and Nrf2 signaling. Analysis of mRNA expression of Pparα-related genes in wild type and Nrf2 knockout (Nrf2-null) mice treated for five days with 250mg/kg CFB suggests that Nrf2 regulates Pparα function. Gene expression of Pparα was not altered basally between wild type and Nrf2-null mice; however, expression was elevated significantly in CFB-treated Nrf2-null mice, compared to wild types. For Pparα-dependent genes analyzed, mRNA levels were significantly increased with CFB treatment in both genotypes. Elevation was significantly higher in CFB-treated Nrf2-null compared to wild types also receiving CFB. This suggests that the ability of Pparα target genes to be induced is heightened in the absence of Nrf2. Also, mRNA expression of Ppar gamma coactivator 1-alpha (Pgc1α) was elevated in Nrf2-null mouse liver, independent of CFB treatment. Altogether, these results are indicative of a potential regulatory link between Nrf2 and Pparα signaling.

Major Advisor

Jose Manautou

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